Project Summary/Abstract The overall goal of this proposal is to foster the development of the candidate as an independent patient-oriented researcher focusing on skeletal muscle pathology associated with chronic kidney disease (CKD) and its functional and metabolic sequelae. The overarching aim of this proposal is to examine how inflammation affects changes in skeletal muscle physiology and physical function in the period surrounding dialysis initiation. The applicant will receive focused mentoring from experts in the study of CKD, muscle physiology, and metabolism and will combine epidemiological and molecular methods to address this question. This study will be the first to prospectively follow patients with advanced kidney disease in a pivotal moment of transition in their care: the initiation of dialysis. We will perform longitudinal measurements of markers of inflammation and important clinical and functional parameters. We will integrate these data with skeletal muscle physiology, and will simultaneously evaluate multiple homeostatic pathways in skeletal muscle in humans. Our aims are: (1) To define the association of inflammation with changes in skeletal muscle physiology, lean body mass, and physical function in patients with advanced predialysis CKD; and (2) To define the effect of the transition to chronic dialysis on inflammation, skeletal muscle homeostasis, lean body mass, and physical function. No studies in patients with CKD have simultaneously examined muscle wasting at a biochemical, physiologic, and clinical level as we propose. This application includes a rigorous 5 year career development plan that includes an integrated strategy of intensive mentorship, formal training in new research methods for studying human physiology, focused didactic coursework, and participation in research seminars and national scientific meetings. A significant portion of this plan is devoted to mastering new research methods that will enable the primary investigator to establish an independent research program at the intersection of kidney disease, muscle metabolism, and physical function. In summary, this proposal will produce important, clinically relevant data and is intended to generate preliminary data for an R01 application studying the effects of anti-inflammatory therapy on muscle wasting in patients with CKD. Intensive, focused, and interdisciplinary mentoring will foster the candidate's development as an investigator with expertise studying mechanisms of muscle atrophy in concert with clinical outcomes. This research proposal has the potential to improve the care of patients with CKD by leading to future innovations in the prevention and treatment of muscle wasting and functional decline.